1. Field of the Invention
The invention generally relates to the treatment of skin conditions such as psoriasis. In particular, the invention provides methods for treating skin, which is either damaged or undamaged, using compositions containing a ubiquinone and an abrasive, and for delivering compositions containing a ubiquinone by means of a transdermal patch.
2. Background of the Invention
The skin provides an essential protective barrier against environmental challenges such as radiation, extremes of temperature, excessive dryness, invasion by infectious organisms, and many others. As such, the maintenance of the health of the skin is of great importance for the overall preservation of well-being. This maintenance includes both preventative skin care and attention to rapid and effective healing of pathological skin conditions.
Much effort has been exerted in understanding the factors which promote healthy skin, especially those factors which are "naturally occurring", i.e. biological substances which are the components of the skin's endogenous protective and healing mechanisms. For example, it is known that the skin possesses an elaborate antioxidant defense system to deal with oxidative stress. Evidence for this is suggested by investigations of skin disorders such as Xeroderma pigmentosum, in which biopsies revealed an abnormally low level of activity of the enzyme catalase, which is involved in the defense against oxygen free radicals. Excessive exposure to environmental insults such as UV radiation can overwhelm the cutaneous antioxidant capacity, leading to oxidative damage and ultimately to skin cancer, immunosuppression, and premature skin aging.
Clinical studies of patients with active vitiligo have revealed diminished levels of several enzymatic and nonenzymatic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, vitamin E, glutathione reductase and polyunsaturated fatty acids in the epidermis. Since the levels of all these substances were depleted, it may reasonably be concluded that these antioxidants act in synergy and that their depletion manifests itself in the attendant skin disorders.
In the treatment of cutaneous wounds it has been observed that the levels of all enzymatic and non-enzymatic antioxidants except for glutathione reductase are severely decreased. In fact, none of these antioxidants except for glutathione were able to recover their normal levels as long as 14 days past wounding.
Hope for the successful treatment of such conditions lies in the identification of protective substances and in understanding their role in healing. One substance which has been implicated is the coenzyme, CoEnzyme Q, also known as ubiquinone, because it is ubiquitous in biological systems. CoEnzyme Q is a quinone derivative with a long isoprenoid tail. The number of 5-carbon isoprene units in the coenzyme is variable. The most common form in mammals contains 10 isoprene units (CoEnzyme Q.sub.10, or COQ.sub.10), but other forms contain up to 15 isoprene units (COQ.sub.15). COQ is the coenzyme for at least three mitochondrial enzymes (Complexes I, II, and III) as well as enzymes in other parts of the cell. These mitochondrial enzymes, which function in the oxidative phosphorylation pathway, are essential for the production of ATP, the energy source upon which all cellular functions depend. The biosynthesis of COQ is known to be a multi-stage process requiring at least eight vitamins and several trace elements.
Through investigative research it has been determined that COQ.sub.10 has beneficial therapeutic effects for many skin disorders due to its antioxidant or free radical quenching properties. Administration of COQ.sub.10 not only greatly reduces antioxidant damage to tissue but also improves the immunocompetance of the cells. These properties can be significantly enhanced by administration in combination with other nonenzymatic and enzymatic antioxidants. Based on a limited number of clinical trials, it has been discovered that COQ.sub.10 works most effectively in the presence of certain vitamins and amino adds. Specifically these are Vitamins A, B.sub.6, C, D, and E, glutathione, carnitine, arginine, taurine, cysteine and methionine. Other ingredients which also significantly improve the therapeutic efficacy of COQ.sub.10 are the enzymes superoxide dismutase (SOD) and catalase, alpha-lipoic/dihydrolipoic acid, and proanthocyanadins. The improved efficacy is believed to be the result of the synergistic effect of each of the components with respect to the healing process. Periodontal disease has also been treated relatively successfully with COQ.sub.10.
Other research has shown that the combination of SOD and glutathione are effective in inhibiting erythema induced by UVB radiation. Further improvement was also noted by the addition of squalene which alleviated skin irritation by suppression of superoxide anion production. Again, the combination of ingredients appears to be more effective than any one alone.
Research has shown that carnitine also enhances the healing of the skin. The application of carnitine to treat refractory venous, mixed, or arterial ulcers resulted in nearly complete regression of trophic lesions in 79% of patients tested. The only apparent side effect was that some patients experienced transitory cutaneous hyperemia at the site of drug injection. From these studies, it was concluded that carnitine would be effective in the treatment of cutaneous ulcers.
Alpha-lipoic acid, which plays an essential role in mitochondrial dehydrogenase reactions, has recently gained considerable attention as an antioxidant. Alpha-lipoic acid and its reduced form, dihydrolipoic acid (DHLA), react with potentially damaging reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals and singlet oxygen. It also protects membranes by interacting with Vitamin C and glutathione. In turn, glutathione enhances the effect of Vitamin E by inhibiting its peroxidation and free radical development. Among several biologically and pharmacologically active sulphur compounds which have been investigated, only alpha-lipoic and dihydrolipoic acid were found to be effective in providing protection to plasmid DNA against singlet molecular oxygen. Since alpha-lipoic acid is both oil and water soluble, it is considered to be the "missing link" between Vitamin E and Vitamin C metabolism.
Topical application of Vitamin E has been shown to modulate the skin's antioxidant network and to diminish ultraviolet induced oxidative damage to the skin. Pretreatment with Vitamin E was shown to increase dermal superoxide dismutase activity, and to protect epidermal glutathione peroxidase and SOD from depletion after exposure to UV radiation. As a result of Vitamin E application, both glutathione reductase and ascorbate levels increased in the skin. In addition, Vitamin E treatment significantly reduced the formation of epidermal lipid hydroperoxides. These results demonstrate that topical application of Vitamin E protects cutaneous tissues against oxidative stress and suggest that the underlying mechanism of this effect involves the up-regulation of a network of enzymatic and nonenzymatic antioxidants.
Melatonin is a natural hormone which is synthesized by the body and exists in every cell. It is derived from serotonin, a neurotransmitter which in turn is converted from an amino acid by the pineal gland. Age adversely affects the ability to synthesize melatonin and this decline is believed to play a prominent role in the aging process.
Melatonin exhibits strong antioxidant properties, particularly with regard to peroxyl and hydroxyl radicals, and there is evidence that it is also a potent inhibitor of nitric oxide. Nitric oxide is believed to play an important role in the stimulation of free radical damage.
Melatonin is a small molecule which is highly diffusable and requires no binding sites or receptors to function. Melatonin has primarily been associated with brain function and has never been used topically to treat skin tissue.
Melatonin protects cells by stimulating glutathione peroxidase which converts reduced glutathione to its oxidized state, thus inhibiting the production of hydroxyl radicals. Melatonin has been used by itself and as adjuvant treatment for cancer, heart disease, stroke and Alzheimer's disease with some successes. It is contended that melatonin stimulates natural antioxidant levels, improves DNA repair and enhances the neuro-endocrine and immune systems. It appears that melatonin, like COQ.sub.10, plays a role as a potent antioxidant and as an immuno stimulant.
There currently does not seem to be any anecdotal evidence of the specific effect melatonin might have on the efficacy of topical skin treatment. However, since melatonin and COQ.sub.10 are both ubiquitous and possess similar properties, it would seem that melatonin, with the advantage of its smaller molecular structure, could be an effective topical agent, either by itself or in synergistic combination with COQ.sub.10 and/or other antioxidants. In Example 12 below, we show that this is indeed the case.
Even though progress has been made with respect to understanding the role of various naturally occurring substances in the healing and health maintenance of skin, especially with respect to the antioxidant properties of those substances, there is still a need for continued investigation. A number of conditions remain refractory to current treatment protocols, such as the highly problematic skin disease psoriasis. There is currently no effective treatment for psoriasis, and such a treatment would be highly beneficial to those who suffer from the condition. Many other skin conditions exist which currently have no really effective means of treatment, including keratosis, rosacea, and the scarring that results from acne vulgaris. For some of these conditions, little or no improvement occurs as a result of current treatment practices.
It would thus be of great benefit to those who suffer from pathological or disfiguring skin conditions of many types to have available improved preparations of substances which could ameliorate those conditions. In addition, it would be of great benefit to have available improved preparations of substances which could be used prophylactically in order to prevent the occurrence of skin damage due to environmental insult and oxidative stress.
Regardless of how many salutary ingredients a pharmaceutical preparation contains, in order to derive maximal benefit from it, the preparation must be administered in an efficacious manner. It would be of benefit to have available more efficient systems for the topical delivery of preparations intended to treat skin disorders.